Paul Lombroso, M.D.

Elizabeth Mear and House Jameson Professor

Research Interests

The Lombroso Lab studies how we normally learn and how these processes are disrupted in various neuropsychiatric disorders. We are interested in a number of disorders including Tourette’s syndrome, obsessive-compulsive disorder, autism, as well as drug addiction and Alzheimer’s disease. Our work focuses on a brain-specific protein tyrosine phosphatase called STEP and its role in regulating intracellular signaling. Studies have shown that STEP regulates ERK1/2 and Fyn by dephosphorylating and inactivating them. STEP also regulates the cell surface expression of AMPA and NMDA glutamate receptors, and leads to their endocytosis. Signals that lead to the inactivation of STEP potentiate learning, while signals that lead to the activation of STEP oppose the development of synaptic plasticity. We use biochemical, molecular, immunocytochemical, and behavioral techniques to address the role that STEP plays in regulating aspects of learning.

Ongoing projects:

• Use of dominant negative STEP proteins to disrupt various learning paradigms.
• Characterization of the STEP knock-out mouse.
• Regulation of glutamate receptor trafficking by STEP.
• Role of STEP in Alzheimer’s disease.
• Regulation of local protein translation.
• Phosphorylation of STEP and function of phosphorylation at specific sites.
• Characterization of major vault protein.

Recent Publications

• Choi YS, Lin SL, Lee B, Kurup P, Cho HY, Naegele JR, Lombroso PJ, Obrietan K. (2007) Status epilepticus-induced somatostatinergic hilar interneuron degeneration is regulated by striatal enriched protein tyrosine phosphatase. J Neurosci 27:2999-3009. [View article]
• Paul S, Olausson P, Venkitaramani D, Ruchkina I,  Moran TD, Mills E,  Tronson N, Hakim S, Salter MW, Taylor J and Lombroso PJ (in press)  The protein tyrosine phosphatase STEP gates long-term potentiation and fear memory in the lateral amygdala. Biological Psychiatry. [PDF]
• Braithwaite S, Paul S, Nairn A, Lombroso, PJ (2006) Learning and  Memory: One STEP at Time. Trends in Neuroscience 29:452-458. [PDF]
• Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC,  Salter MW, Lombroso PJ, Gouras GK, Greengard P (2005) Regulation of  NMDA receptor trafficking by beta-amyloid. Nature Neuroscience  8:1051-1058. [PDF]
• Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H, Corvol J- C, Stipanovich A, Caboche J, Lombroso PJ, Nairn AC, Greengard P, Herve D, Girault J-A (2004) Regulation of a protein phosphatase  cascade allows convergent dopamine and glutamate signals to activate  ERK in the striatum. PNAS 102:491-496. [PDF]
• Paul S, Nairn A, Wang P, Lombroso PJ (2003) NMDA-mediated  activation of the protein tyrosine phosphatase, STEP, regulates the  duration of ERK signaling. Nature Neuroscience 6:34-42. [PDF]
• Nguyen TH, Liu J, Lombroso PJ (2002) Striatal enriched phosphatase  61 (STEP61) dephosphorylates Fyn at phosphotyrosine 420. JBC  277:24274-24279. [PDF]
• Pelkey K, Askalan R, Paul S, Kalia LV, Nguyen T-H, Pitcher GM,  Salter MW, Lombroso PJ (2002) Tyrosine phosphatase STEP is a tonic  brake on induction of long-term potentiation. Neuron 34:127-138. [PDF]
• Paul S, Hisayuki Y, Snider G, Picciotto M, Nairn A, Lombroso  PJ (2000) Dopamine/D1 receptor mediates the phosphorylation and  inactivation of the protein tyrosine phosphatase, STEP, through a PKA- mediated pathway. J Neuroscience 20:5630-5638. [PDF]
• Bult A, Zhao F, Dirkx R, Sharma E, Lukacsi E, Solimena M, Naegele  JR,, Lombroso PJ (1996) STEP61: A new member of a family of brain- enriched PTPs is localized to the ER. J Neuroscience 16:7821-7831. [PDF]

Contact

Campus Address
Child Study Center
230 South Frontage Road
P.O. Box 207900
New Haven, CT 06520-7900

Office Address
SHM I-270

E-mail
paul.lombroso@yale.edu

Office Phone
203.737.2224

Fax
203.785.7611